GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (13)
  • English  (13)
  • 2015-2019  (13)
Material
Publisher
  • American Association for Cancer Research (AACR)  (13)
Person/Organisation
Language
  • English  (13)
Years
  • 2015-2019  (13)
Year
Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Abstract PR05: Exceptional Response to PD-1 antibody treatment in a POLE-mutant endometrial cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. PR05-PR05
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. PR05-PR05
    Abstract: Genomic assessment of exceptional responders is a promising approach to identify predictors of response to antibody therapy directed against the immune checkpoint programmed death 1 (PD-1) receptor, which has been shown to yield prolonged and deep responses in multiple types of human cancer. We identified a patient with endometrial cancer who experienced an exceptional response to pembrolizumab, an antibody to programmed death 1 (PD-1) receptor. The primary endometrial cancer specimen and the biopsy from the recurrent supraclavicular lymph node (LN) metastasis obtained prior to treatment were analyzed by hybrid-capture based genomic profiling at a commercial CLIA-certified laboratory, Foundation Medicine, targeting all exons of 315 cancer-related genes. In the patient's pre-treatment endometrial cancer specimens we identified a mutation in DNA polymerase epsilon gene (POLE), which is associated with disruption of the exonuclease activity required for proofreading function and results in a high mutation burden or “ultramutator” phenotype. This tumor did harbor a large number of mutations: 32 likely pathogenic sequence variants and 116 variants of unknown significance (VUS). We next reviewed genomic alterations in 252 deidentified endometrioid endometrial cancers that underwent genomic profiling with the FoundationOne assay and determined that 23 (9.1%) had sequence variants in POLE. The cancers with POLE sequence variants had a mean of 21.2 +/-4.1 mutations identified as likely pathogenic and 82.2 +/-25 variants identified as VUS, compared with a mean of 7.5+/-0.5 likely pathogenic variants and 12.8 +/- 2.6 VUS in POLE wt cases (mean +/- S.E.; p & lt;0.005 and P = 0.015, respectively). This is consistent with TCGA data showing that POLE mutant cancers typically harbor an extremely high mutational burden. To determine if POLE mutant cancers were associated with an immune signature, analysis of RNA sequencing data from endometrioid endometrial cancers in TCGA was performed. POLE mutant cancers have higher expression of several genes encoding for immune checkpoint-related proteins, including PD-L1 and PD-L2, than either MSI or MSS endometrioid cancers. POLE mutant cancers also showed higher expression of T-cell markers such as CD8A, CD3G, PD-1 and CTLA-4, suggesting the presence of a pre-existing T-cell infiltrate. Analysis of histologic image data from TCGA confirmed that POLE mutant cancers had presence of a robust lymphocytic infiltrate. These data suggest that endometrial cancers harboring POLE mutations are associated with expression of immune checkpoint genes and evidence of lymphocytic infiltration. Thus, these tumors may be exceptionally vulnerable to treatment with immune checkpoint inhibitor therapy. We propose further clinical investigation with immunotherapy in endometrial and other cancers with POLE mutations. Citation Format: Janice M. Mehnert, Anshuman Panda, Hua Zhong, Kim M. Hirshfield, Sherri Damare, Katherine Stiles, Levi Sokol, Mark N. Stein, Lorna Rodriguez-Rodriguez, Howard L. Kaufman, Siraj Ali, Jeffery Ross, Dean C. Pavlick, Gyan Bhanot, Eileen P. White, Robert S. DiPaola, Ann Lovell, Jonathan Cheng, Shridar Ganesan. Exceptional Response to PD-1 antibody treatment in a POLE-mutant endometrial cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR05.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-PR05
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 212: Identification by mass spectrometry of unique phosphoproteins subsequent to signaling through c-ErbB2
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 212-212
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 212-212
    Abstract: The receptor tyrosine kinase c-ErbB2 is amplified in breast and ovarian cancer. The linear pathways through which signals by c-ErbB2 are transduced is well known. However, second generation questions that address spatial aspects of signaling remain. To address this, we have undertaken a mass spectrometry approach to identify phosphoproteins. We have used two tyrosine kinase inhibitors, Lapatinib and CP724714, that inhibit phosphorylation of c-ErbB2 to identify phosphoproteins. SKOV-3, an ovarian cancer cell line that endogenously overexpresses c-ErbB2 was grown in culture without serum for 72 hrs. Cells were then stimulated in the presence or absence of inhibitor with EGF (100ng/ml) as a ligand for 60 mins. Subsequently, cells were lysed and evaluated by western blotting with anti-phosphotyrosine antibody (4G10). Following stimulation of cells with EGF, maximal phosphorylation of c-ErbB2 was observed at 60 minutes. Lapatinib (10μM) and CP724714 (15μM) completely inhibited phosphorylation of c-ErbB2, which was confirmed by immunoprecipitation. This was further confirmed by the inhibition of downstream effectors (Erk1/2, Akt). Lapatinib (10 μM) also completely inhibited phosphorylation of EGFR while CP724714 (15μM) only inhibited partially. Cellular lysates were prepared from quiescent cells (grown without serum), after stimulation with EGF in the presence or absence of inhibitors. Purified phosphoproteins from all three samples following digestion with trypsin were subjected to mass spectrometry (Nano LC ESI MS/MS). We identified totally 62 phosphoproteins. Twenty seven phosphoproteins were observed in all the 3 samples while 17 phosphoproteins were identified both in the EGF stimulated and lapatinib treated samples. Eighteen unique phosphoproteins were observed only in the EGF stimulated sample suggesting that they are specific to signaling by c-ErbB2. The novel phosphoproteins included the proteins that partcipate in carbohydrate metabolism,cytoskeleton, cell migration and proliferation. We have evaluated two phosphoproteins, LASP-1 and Aldose reductase that has not been previously described following phosphorylation of c-ErbB2. LASP-1 is an oncogene and is located as the same arm 17q21 as c-ErbB2. It was not expressed in the normal ovary or fallopian tube. However, it was over-expressed in 17% of tumours (n=85) from patients with ovarian cancer. c-ErbB2 was not expressed in tumours that expressed LASP1. Aldose reductase is a cytosolic NADPH dependent oxidoreductase that catalyzes the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism. The activity of aldose reductase in reducing NADPH as a substrate was significantly higher in lysates from EGF stimulated as compared to the starved cells. Identification of phosphoproteins by using mass spectrometry is promising in identifying novel substrates and pathways following phosphorylation of c-ErbB2. Citation Format: C Sidhanth, Manoj Garg, P Manasa, S Krishna Priya, S Bindhya, S Sneha, R.P. Nagare, S Shirley, M Kanchan, Trivadi S. Ganesan. Identification by mass spectrometry of unique phosphoproteins subsequent to signaling through c-ErbB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 212. doi:10.1158/1538-7445.AM2017-212
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-212
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 4463: Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4463-4463
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4463-4463
    Abstract: Metabotropic glutamate receptor 1 (GRM1) has an established oncogenic role in melanoma. Growing evidence supports a similar role in breast cancer. We have previously shown that GRM1 is not only expressed in human breast cancers, but that levels of expression correlate with clinical outcomes with tamoxifen treatment, and that GRM1 knockdown reduces breast cancer cell viability and growth. Others have shown that GRM1 modulating drugs also reduce viability and growth of estrogen receptor (ER) negative breast cancer cell lines. Riluzole, a postulated inhibitor of glutamate release, has been evaluated in pre-clinical studies in melanoma. Early clinical trials have shown promising results for this disease. However, the mechanistic effects of riluzole have not been well-defined. Therefore, we evaluated the functional activity of riluzole in breast cancer. A molecularly diverse set of ER+ and ER- breast cancer cell lines with variable GRM1 expression were evaluated. Cell lines were treated with either riluzole or BAY 36-7620 (non-competitive GRM1 antagonist) or their combination. Treatment with either drug reduces cell number and viability, inhibits cell proliferation, and alters expression of cell cycle and apoptotic pathway genes as determined by gene microarray analysis. Drug treatment produces cell line-dependent effects on markers for proliferation, cell cycle, DNA damage, and apoptosis. Riluzole induces G2/M arrest in all cell lines tested. More specifically, riluzole induces mitotic arrest as demonstrated by changes in histone H3 phosphorylation at serine 10 and cyclin B level. Treatment with BAY 36-7620 induces a modest G2/M arrest and increase in the sub G1 population in a subset of cell lines. However, BAY 36-7620 does not induce mitotic arrest. The combination of riluzole and BAY 36-7620 results in increased cell death and decreased proliferation in all cell lines tested. Our data suggest that either riluzole or BAY 36-7620 induce breast cancer cell death. However, riluzole may modulate the activity of intracellular targets independent of GRM1. As riluzole is an FDA-approved drug, it could be quickly moved into a clinical trial and may provide a novel therapeutic approach in the treatment of breast cancer. Citation Format: Sonia C. Dolfi, Daniel J. Medina, Shridar Ganesan, Alexei Vazquez, Kim M. Hirshfield. Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4463. doi:10.1158/1538-7445.AM2015-4463
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4463
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract 182: Cancer stem cells and tumor angiogenesis in serous adenocarcinoma of ovary
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 182-182
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 182-182
    Abstract: The traditional view of tumour vascularization is that tumours acquire blood supply from the neighbouring normal stroma. However, recently the origin of tumour endothelial cells or pericytes in part has been shown to be derived from cancer stem cells (CSCs) in glioblastoma. In high grade serous ovarian cancer (HGSOC), the origin of endothelial cells is not known. Our objective was to determine if components of a tumour blood vessel and lymphatic vessel are derived from CSCs in ovarian cancer. Using spheroids as an in vitro model, we have evaluated the role of CSCs in primary malignant cells (PMCs) from patients with serous adenocarcinoma of ovary cultured under specific conditions. The expression of endothelial, pericyte and lymphatic endothelial markers was evaluated by flow cytometry. In addition, functional assays were performed to assess the endothelial phenotype. Further, the ability of CSCs to express endothelial markers under appropriate growth conditions was also evaluated with Bevacizumab which antagonize VEGF. PMCs grown in endothelial growth medium (EGM) showed significantly higher expression of CD105 (n=32, p = 0.002) and CLEC14A (n=10, p = 0.012) and co-expression of CD105/CLEC14A (n=10, p= 0.012) than that of spheroids. Primary malignant cells when grown in pericyte and lymphatic endothelial specific conditions, showed significantly higher expression of desmin (n=10, p=0.03), Smooth muscle actin (SMA) (n=10, p=0.017) and VEGFR3 (n=10, p=0.028) than that of the spheroids. When the PMCs were grown as spheroids in endothelial conditions in the presence or absence of Bevacizumab (1 μg/μl), there was a reduction in the co-expression of CD105 and CLEC14A (P=0.04). The cells grown in endothelial conditions showed formation of tubes, uptake of Dil-ac-LDL and expressed eNOS, confirming their endothelial phenotype. GFP transduced spheroids from PMCs formed tumours in mice and the blood vessels in the tumour co-expressed CD31, SMA, VEGFR3 and GFP, suggesting that these cells are derived from CSCs. These results prove that a proportion of endothelial cells, pericytes and lymphatic endothelial cells are derived from CSCs in serous ovarian carcinoma and the VEGF pathway has a key role. This property of CSCs to contribute to tumour angiogenesis can be inhibited. Citation Format: S Krishnapriya, C Sidhanth, P Manasa, S Sneha, S Bindhya, R P. Nagare, T S. Ganesan. Cancer stem cells and tumor angiogenesis in serous adenocarcinoma of ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 182.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-182
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract P1-15-14: Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P1-15-14-P1-15-14
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P1-15-14-P1-15-14
    Abstract: Background: The use of neoadjuvant platinum with taxane for triple negative breast cancer (TNBC) has gained increased attention for improving rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects while allowing for greater platinum dosing compared to a taxane combination. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and that tumor genomics may aid in determining those patients most likely to benefit. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Tumor genomic profiling was done to determine the mutational spectrum, association of this spectrum in primary tumors with achieving pCR, and identifying alternative treatment strategies for PDX evaluation for patients with resistant disease. Results: From 2/2015 to 5/2018, 36 pts were enrolled and 32 completed treatment; 4 pts await definitive surgery; 12 (33%) are two years from diagnosis. Median age of the cohort was 53 years. There was high participation by under-represented groups: 23% African American, 20% Asian, 14% Hispanic. Most histologies were invasive ductal but included apocrine, pleomorphic lobular, and metaplastic subtypes. Of the 32 pts who completed surgery, 34% (11) achieved pCR and 64% (23) had clinical response on serial physical exam. At 2 years, there were 2 distant and 1 local recurrence. The most common toxicities during DOX+CAR were grade 1 nausea in 19 pts (53%), grade 3/4 neutropenia occurred in 10 pts (28%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (3%) in this group. Grade 3 thrombocytopenia (2 pts), pruritis (1 pt), and mucositis (1 pt) were observed. Only 6 pts (17%) had grade 1 alopecia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. TP53 (93%), PI3K/PTEN (26.6%), and NOTCH (20%) were the most commonly altered pathways. Structural variants, such as amplifications, rearrangements, and frameshifts were the most frequent alterations detected. Of the 25 pts who had residual disease, PDX was attempted from 14 pts, and 10 (71%) PDX were established, including those for all 3 patients experiencing recurrence. Conclusion: Neoadjuvant DOX+CAR demonstrated good efficacy and tolerability. Post-chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Chan N, Riedlinger GM, Lu S-e, Pham KT, Kirstein LJ, Eladoumikdachi FG, George MA, Potdevin LB, Kowzun MJ, Desai SA, Tang DM, Omene CO, Wong ST, Rodriguez-Rust L, Kumar S, Kearney TJ, Liu C, Ganesan S, Toppmeyer DL, Hirshfield KM. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-14.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P1-15-14
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract 3330: Tumor angiogenesis and cancer stem cells in serous adenocarcinoma of the ovary
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3330-3330
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3330-3330
    Abstract: Angiogenesis is required for tumor growth and metastasis. The conventional view of tumour angiogenesis is that tumours get their blood supply from the neighbouring normal stroma. However, recently the origin of tumour endothelial cells or pericytes in part has been shown to be derived from cancer stem cells (CSC) in glioma. The spread of ovarian cancer (SOC) is different and the origin of endothelial cells in the tumor is not known. Using spheroids as an in vitro model (which is enriched for CSC), we have evaluated the role of CSC in primary malignant cells (PMCs) from patients with serous adenocarcinoma of ovary (n = 30) cultured under endothelial conditions. The expression of endothelial markers (CD31, CD105, and CLEC14a) was evaluated by flow cytometry. Further, the ability of CSC to express endothelial markers under appropriate growth conditions was also evaluated with Bevacizumab (Avastin) or Cediranib which antagonize VEGF or its receptor (VEGFR2) respectively. In addition, functional assays such as uptake of Dil labelled acetylated low density lipoprotein (Dil-ac-LDL) and expression of endothelial nitric oxide synthase (e-NOS) was performed to assess the endothelial phenotype. The localization of tumour blood vessels and CSC in primary ovarian tumors was examined by double immunohistochemistry of CD31/CD105/CLEC14a and ALDH1a1. Primary malignant cells (n = 30) grown in endothelial growth medium (EGM) showed significantly higher expression of CD105 (mean 20.8%, p = 0.001) and CLEC14a (mean 5.3%, p = 0.012) and a co-expression of CD105/CLEC14a (mean 1.6%, p = 0.012) than that of control (mean, 12.5%, 2.5% and 0.95% respectively). The co-expression of ALDH1a1 with endothelial markers, CD31, (mean, 1.58%), CD105, (mean 0.7%), CLEC14a (mean 0.44%) in primary malignant cells (n = 5), denovo, suggest that there is a small proportion of cells which are in transit to form endothelial cells. When the primary malignant cells were grown as spheroids in endothelial conditions in the presence or absence of Avastin (1 μg/μl), there was reduction in the expression of CD105 (mean, 12.5% (EGM) and 7.9% (Avastin), P = 0.056) and CLEC14a (mean. 5.5% (EGM) and 1.5% (Avastin), P = 0.04). However, when the spheroids were cultured in presence of cediranib (10 nM), the expression of CD105 was not reduced (Mean, 2.53% (EGM) and 4% (cediranib). The cells grown in endothelial conditions showed uptake of Dil-ac-LDL (n = 3) and expressed e-NOS (n = 3), confirming their endothelial phenotype. The double immunostaining with ALDH1a1 and CD31/CD105 demonstrated that the blood vessels were in proximity to ALDH1A1+ cells in primary serous adenocarcinoma of the ovary (n = 5). These results suggest that a proportion of endothelial cells (probably 20%) could be derived from CSC in serous ovarian carcinoma and the VEGF pathway has an important role. This property of CSC to contribute to tumour angiogenesis can be inhibited. Citation Format: Syama Krishna Priya, Rohit P. Nagare, V S. Sneha, C Sidhanth, S Bindhya, P Manasa, Trivadi S. Ganesan. Tumor angiogenesis and cancer stem cells in serous adenocarcinoma of the ovary. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3330.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3330
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    TGFβ Promotes Genomic Instability after Loss of RUNX3
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 1 ( 2018-01-01), p. 88-102
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 1 ( 2018-01-01), p. 88-102
    Abstract: Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFβ is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFβ also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFβ-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell–extrinsic TGFβ signaling and cancer cell–intrinsic RUNX3 inactivation as aggravating factors for genomic instability. Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. Cancer Res; 78(1); 88–102. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-1178
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Abstract 4129: Novel oncogenic BRAF fusions and impact on targeted therapies
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4129-4129
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4129-4129
    Abstract: BRAF mutations are driver events in a number of cancers including thyroid cancer and melanoma. The most common, BRAF V600E, alters normal BRAF protein activity in the mitogen-activated protein kinase (MAPK) pathway by constitutively activating BRAF and inducing proliferative signaling and tumor growth. Small molecule tyrosine kinase inhibitors targeting tumors with the V600E mutation have been evaluated in clinical trials and are now approved for melanoma. While BRAF missense mutations have been extensively characterized for oncogenic potential and actionability in genomically-guided therapy, BRAF gene fusions have been underappreciated for not only their functional role in cancer but also in differential drug response. More recently, data suggest that alternative approaches may be needed for treatment of patients with BRAF fusion-containing tumors. We have identified two novel BRAF fusions in tumors from patients with papillary thyroid cancer and melanoma. Both fusions result in an in-frame fusion of a novel gene partner at the 5’ end of the fusion, an intact BRAF kinase domain at the 3’ end, and loss of the BRAF auto-inhibitory domain. We hypothesized that these novel BRAF fusions act as oncogenic drivers, and the mechanism of BRAF activation differs from that caused by V600E mutations and may be fusion partner-specific. These fusions have been engineered in the laboratory and tested for tumorigenic potential and functional activity. BRAF fusion expression in non-transformed cells induces colony formation similar to the V600E mutation indicating tumorigenic potential. These BRAF fusions also constitutively activate the MAPK pathway in the absence of stimulation as demonstrated by phosphorylated ERK and MEK proteins. Additionally, BRAF fusion-expressing cells form tumors in vivo similarly to the BRAF V600E-expressing cells. These tumors are highly proliferative as demonstrated by strong Ki67 immunohistochemical staining and display MAPK pathway activation as evidenced by phosphorylated ERK. BRAF fusion-expressing cells have differential sensitivity to MAPK pathway inhibitors compared to cells with the V600E mutation as measured by reduced MAPK signaling. Inhibition of the MAPK pathway is relevant in targeting BRAF fusion-containing cells but may not follow the same paradigm as point mutations. Collectively, our data suggest that BRAF fusions are functional and represent novel therapeutic targets, but may need an alternative approach as compared to tumors with BRAF missense mutations. Citation Format: Sonia C. Dolfi, Ann Silk, Bhavna Paratala, Whitney Petrosky, Srilatha Simhadri, Atul Kulkarni, Shridar Ganesan, Kim M. Hirshfield. Novel oncogenic BRAF fusions and impact on targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4129. doi:10.1158/1538-7445.AM2017-4129
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-4129
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract 3693: GLIS1 can replace MYC to generate induced pluripotent stem cells from ovarian cancer cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3693-3693
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3693-3693
    Abstract: Ovarian cancer is the most common cause of mortality among gynecological cancers, despite advances in treatment. Recurrence is common and is due to development of drug resistance. One of the reasons for drug resistance is the persistence of cancer stem cells. To understand the role of CSCs, it is essential to capture and propagate cells continuously in culture. Reprogramming cancer cells to induced pluripotent stem cells (iPSCs) is an approach to achieve this. An ovarian cancer cell line, PEO4 (high grade serous adenocarcinoma), was initially reprogrammed into iPSCs using the classical four factors OCT4, SOX2, KLF4 and MYC (OSKM) using STEMCCA by lentivirus transduction. Embryonic stem cell (ESC)-like bodies appeared between 8 to 15 days post-transduction. Morphology of the colonies resembled that of ESC colonies with defined border and tightly-packed cells. Two individual clones were further characterized. The reprogrammed PEO4-OSKM-iPSCs expressed alkaline phosphatase and pluripotency markers, NANOG, OCT4, SSEA4, TRA-1-60 and TRA-1-81 by immunofluorescence. Further, reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis showed expression of the pluripotency markers NANOG, SOX2, OCT4, TERT, NESTIN, DMNT, DPPA4 in PEO4-OSKM-iPSC which were absent in the parental PEO4 cells. PEO4-OSKM-iPSC cells could be differentiated in vitro with appropriate growth factors into ectodermal, mesodermal and endodermal lineages. MYC was replaced with GLIS1 in the lentiviral cassette and PEO4 cells were able to be transformed to iPSCs. The transfection efficiency was two fold better with OCT4-SOX2-KLF4-GLIS1 with larger colonies. Individual iPSC colonies expressed all pluripotency markers and were able to differentiate into all 3 lineages. Characterization of iPSC cells for expression of cell surface markers specific for serous adenocarcinoma, showed that CD133, EPHA1, CD44 and LGR5 were expressed. Cell viability assays demonstrated that IC50 of cisplatin in parental PEO4 cells (15uM) was less as compared to iPSC cells (32uM) (p & lt;0.03) and similarly, IC50 of paclitaxel was less in parental PEO4 (17 uM) as compared to iPSC cells (27 uM) (p & lt;0.02). These results demonstrate for the first time that an ovarian cancer cell line derived from a patient with high grade serous adenocarcinoma can be reprogrammed. Further, GLIS1 can successfully replace MYC as a transcription factor to generate induced pluripotent stem cells. Citation Format: S Bindhya, C Sidhanth, S Krishnapriya, R P. Nagare, M Garg, T S. Ganesan. GLIS1 can replace MYC to generate induced pluripotent stem cells from ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3693.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3693
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Abstract P6-20-05: Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P6-20-05-P6-20-05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P6-20-05-P6-20-05
    Abstract: Triple negative breast cancer (TNBC) is an aggressive subset for which novel therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc Metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate a class of zinc deficient mutant TP53 alleles by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using genetically engineered murine mammary tumor models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival in mice bearing tumors harboring the zinc deficient Trp53R172H allele but not the Trp53 null allele. We synthesized a novel formulation of ZMC1 (Zn-1), in which the drug is made in complex with zinc to improve zinc delivery, and demonstrate that Zn-1 has increased efficacy over ZMC1. Furthermore, we show that ZMC1 plus olaparib is a highly effective combination for tumors expressing the p53R172H mutant. In conclusion, we have validated preclinically a novel therapeutic approach for BRCA1 deficient breast cancer through reactivation of mutant p53. Citation Format: Na B, Yu X, Wither T, Gilleran J, Yao M, Foo TK, Chen C, Moore D, Xia B, Lin Y, Kimball D, Ganesan S, Carpizo D. Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P6-20-05
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...